Invasive, metastatic, and/or drug resistant cancers are responsible for most cancer deaths. Development of a drug that blocks these phenotypes to improve outcomes is the ultimate objective. The specific means is by inhibiting the acidification of extra-cellular and extra-tumoral environments that otherwise facilitates invasion, metastasis, and drug resistance. The lead, RD203, potently inhibits the V-ATPase pump largely responsible for acidification and shows compelling anticancer activities. However, it requires continuous infusion for in vivo efficacy, an impediment to further development. Synthesis and testing of prod rugs of RD203 that mimic the exposure and compelling in vivo efficacy of continuous infusion is the challenging innovation and overall objective of this proposal. RD203 will be synthesized and used to prepare several types of each of three classes of prod rugs designed to release free RD203 slowly and/or target release at the tumor site. The modifications were selected for safety, develop-ability, and precedence in previous clinical development. The prodrugs will be screened and winnowed down by testing for useful: (a) chemical stability, (b) MTD, (c) desired pharmacokinetic profile, and (d) in vivo efficacy with daily doses. From this process one or two RD203 prodrugs will be selected for further development. Provide